1. Technical Field
The invention relates to the treatment of renal diseases using modulators of integrin linked kinase.
Progressive renal disease is an increasingly common and economically burdensome disease. A significant portion of patients progress to acute renal failure, a life threatening illness whose mortality has remained high despite the introduction of its only nonsurgical treatment, hemodialysis, about 25 years ago. Conventional hemodialysis mimics the filtration function of the kidneys by circulating a patient's blood through or over a dialysate solution physically separated from the blood by a porous or permeable wall or membrane. The process results in the preferential diffusion of small molecules, such as urea, from the bloodstream into the dialysate solution.
Although dialysis has dramatically changed the prognosis of renal failure, it is not a complete replacement therapy, since it only provides filtration function and does not replace the homeostatic, regulatory, and endocrine functions of the kidney. Patients on dialysis continue to have major medical problems.
In the United States, kidney failure is experienced by more than 360,000 people who depend on dialysis or a kidney transplant to survive. The number of people with kidney failure has actually doubled over the past 10 years, and the pool of candidates is large. Conservatively estimated, 10.9 million Americans have kidney disease and face the possibility of a future on dialysis or with a kidney transplant. Even with these remarkable treatments, nearly 58,000 people with kidney failure died in 1997. Jones, C. A., et al., Serum creatinine levels in the US population: third national health and nutrition examination survey. American Journal of Kidney Diseases, vol. 32, no. 6, pp. 992-999, December 1998.
Chronic renal failure may result from any major cause of renal dysfunction. The most common cause of end-stage renal disease is diabetic nephropathy, followed by hypertensive nephroangiosclerosis and various primary and secondary glomerulopathies. Plasma concentrations of creatinine and urea (which are highly dependent on glomerular filtration) begin a nonlinear rise as the renal function diminishes. Changes in creatinine and urea concentrations are minimal early on; later levels increase rapidly and are usually associated with systemic manifestations. For substances that are excreted mainly through distal nephron secretion, e.g., K, adaptation usually produces a normal plasma concentration until advanced failure occurs.
Kidney function depends on an intact glomerular filtration unit, allowing the excretion of potentially hazardous small molecular substances but retaining essential macromolecules. The permselectivity of the glomerular filter is defined by a fenestrated endothelial cell layer, the glomerular basement membrane (GBM), and podocytes. The podocyte forms the filtration slit, an ultrastructural membrane bridging the delicate web of interdigitating podocyte foot processes.
In glomerular disease there is progressive podocyte damage and proteinurea. Although the mechanisms for the progression of renal impairment remain fully undetermined, available evidence indicate that renal glomerular hypertension is responsible in part for the development of renal injury. In renal disease, afferent arteriolar tone is reported to be reduced, while the augmented intrarenal angiotensin II serves to act as an efferent arteriolar constrictor, both of which result in an increase in glomerular capillary pressure. Angiotensin converting enzyme inhibitors (ACE-I) are established as the agent possessing both antihypertensive and renoprotective actions, which exert vasodilator action on efferent arterioles. Calcium antagonists are also reported to have salutary effect on renal disease, although their beneficial action varies depending on the antagonists used and the underlying disease. Chronic progression can be slowed for 6-12 months using these drugs, but there is no other treatment at this time besides dialysis and ultimately transplantation of the organ.
A long-term replacement therapy which replaces all of the functions of the kidney and which is less costly than current dialysis therapies is desirable.
2. Description of the Related Art
Integrin-linked kinase (ILK) is a receptor-proximal protein kinase regulating integrin-mediated signal transduction. The ILK sequence is described in U.S. Pat. No. 6,013,782, herein incorporated by reference. The presence of ILK mRNA in proteinurea models and puromycin-induced podocyte damage is disclosed by Teixeira et al. (2000) Kidney & Blood Pressure Research 23(3-5):231; Unschuld et al. (1999) Kidney & Blood Pressure Research 22(4-6):400; Kretzler et al. (1998) Kidney & Blood Pressure Research 21(2-4):145. The distribution and regulation of ILK in normal and diabetic kidneys is discussed by Guo et al. (2001) Am J Pathol 159:1735-1742.